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A MULTICENTRE, RANDOMIZED, NON-INFERIORITY TRIAL COMPARING THE EFFICACY OF DEFERIPRONE VERSUS DEFERASIROX IN PEDIATRIC PATIENTS AFFECTED BY TRANSFUSION-DEPENDENT HEMOGLOBINOPATHIES (DEEP-2 TRIAL)

S144

Kattamis, A.1; Felisi, M.2; Reggiardo, G.3; El-Beshlawy, A.4; Bejaoui, M.5; Sherief, L.6; Christou, S.7; Cosmi, C.8; Della Pasqua, O.9; Del Vecchio, G. C.10; Filosa, A.11; Hassab, H.12; Kreka, M.13; Origa, R.14; Putti, M. C.15; Spino, M.16; Telfer, P.17; Tempesta, B.18; Tsang, Y. C.19; Zaka, A.20; Tricta, F.19; Bonifazi, D.18; Ceci, A.21; Maggio, A.22

doi: 10.1097/01.HS9.0000558796.60825.05
Simultaneous Sessions I: Advances in the management of thalassemia
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1First Department of Pediatrics, National and Kapodistriam University of Athens, Athens, Greece

2Consorzio per Valutazioni Biologiche e Farmacologiche, Pavia

3Biostatistics and Data Management Unit, Medi Service, Genoa, Italy

4Pediatric Hospital, Cairo University, Cairo, Egypt

5Pediatrics, Bone Marrow Transplantation Centre, Tunis, Tunisia

6Pediatric, Faculty of Medicine, Zagazig Univeristy, Zagazig, Egypt

7Thalassaemia Center, Hospital Archibishop Makarios III, Nicosia, Cyprus

8Clinica Pediatrica, AOU Sassari, Sassari, Italy

9Clinical Pharmacology & Therapeutics Group, University College London, London, United Kingdom

10U.O. Pediatrica “B. Trambusti”, A.O.U. Consorziale Policlinico-Giovanni XXIII, Bari

11UOSD Malattie rare del globulo rosso, AORN “A. Cardarelli”, Napoli, Italy

12Department of Pediatrics & Clinical Research Center, Faculty of Medicine, Alexandria University, Alexandria, Egypt

13Pediatrics, University Hospital Center “Mother Teresa”, Tirana, Albania

14DH Talassemia, Ospedale Pediatrico Microcitemico “A.CAO, A.O. ”G.Brotzu“, Cagliari

15Department of Woman's and Child's Health (DSDB), University Hospital, Padova, Italy

16ApoPharma Inc., Toronto, Canada

17Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, United Kingdom

18Consorzio per Valutazioni Biologiche e Farmacologiche, Bari, Italy

19Medical Affairs, ApoPharma Inc., Toronto, Canada

20Center of Thalassemia, Hospital”Ihsan Cabej”, Lushnje, Albania

21Fondazione per la Ricerca Farmacologica Gianni Benzi Onlus, Valenzano

22Department of Hematology and Rare Diseases of P.O. “V. Cervello”, Azienda Ospedaliera Ospedali Riuniti “Villa Sofia-Cervello”, Palermo, Italy

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Background:

While the efficacy and safety of deferiprone (DFP) in adult patients with transfusion-dependent hemoglobinopathies (TDH) has been extensively studied, data in children are sparse.

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Aims:

We report results of DEferiprone Evaluation in Pediatrics-2 (DEEP-2), (EudraCT Number 2012-000353-31), a Phase III multicentre, randomized, open label study funded by the EU FP7 Research Program, to compare the efficacy of DFP liquid formulation versus deferasirox dispersible tablets (DFX).

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Methods:

DEEP-2 was a non-inferiority, 12-months, active-controlled trial that included TDH patients, including sickle cell disease (SCD), of 1 month to < 18 years of age. The primary composite efficacy endpoint was treatment success rate based on changes in serum ferritin (SF) levels (all patients) and cardiac iron concentration (MRI-T2*) (patients >10 years able to undergo MRI). Predefined criteria (Figure) were used to determine treatment success for the per protocol (PP) population. The secondary endpoints were changes in SF level, cardiac MRI-T2*, liver iron concentration-R2 (LIC-R2) and safety profile. Non-inferiority (NI) was based on the 2-sided 95% confidence interval (CIL, CIU) of the difference in the success rate between the two arms and was established if CIL was greater than −0.125. In the intention-to-treat (ITT) analysis, treatment failure was strictly assigned to patients who withdrew from the study, irrespective of the ferritin response observed at the time of the study suspension.

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Results:

21 sites from 7 countries participated in the trial between 3/2014 and 9/2017. 393 patients were randomized (1:1 DFP vs. DFX) and included 117 patients < 6 years of age (30%), 38 with non β-thalassemia TDH (mainly SCD) and 54 chelation-naïve. DFP was non-inferior to DFX based on the PP population (n = 271) while the NI criterion was not met for the ITT population (n = 390) due mainly to more patient withdrawals in the DFP arm, which were not mandated by the protocol (Figure). After 1year treatment (PP population) SF changed from 2468 to 2120 ng/ml in DFP arm and from 2822 to 2328 ng/ml in the DFX arm. Cardiac MRI T2* values changed from 31.3 to 32.4ms and from 30.8 to 32.0ms in DFP and DFX arm, respectively. Statistical analysis of the change in SF at the end of treatment also showed NI of DFP for the PP population (δ = −20, CIU = 317 ng/ml; NI criterion: <400 ng/ml), but not for the ITT population when missing SF levels were not analyzed. No significant differences were seen between treatment arms for changes in MRI-T2* and LIC. Overall, there were no statistically significant differences between the two arms in serious adverse events (SAEs) and drug-related SAEs. 18 (9.3%) DFP and 11 (5.5%) DFX-treated patients were reported with neutropenia, 3 reversible cases of agranulocytosis were detected in DFP arm, and 2 reversible renal failures in DFX arm.

Figure

Figure

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Summary/Conclusion:

This FP7-sponsored trial on chelation therapy in pediatric patients with TDH is the largest in this age group and the only one comparing the two oral chelating agents. The results of the study show that 1) oral iron chelation treatment is effective even in very young ages, 2) treatment with DFP was not inferior to DFX in patients who received 12 months treatment, 3) NI was not shown in the ITT analysis partially due to a different rate of withdrawal not necessarily mandated by the protocol, 4) the overall safety profile of both DFP and DFX was acceptable. The results of the DEEP-2 trial provide evidence to support the use of DFP in pediatric patients.

Copyright © 2019 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.